Abstract: Epigenetics is defined as heritable changes in cellular and organismal phenotypes that do not alter the underlying genetic information. In recent years, epigenetic regulation has attracted much attention because it lies at the core of various pathways critical for normal development and pathological progression. Epigenetic processes are especially important for the maintenance of stem cells and their differentiated progenies, as well as for the initiation and pathological progression of various cancer types. Robust methods are available to detect epigenetic states on a genome-wide scale, but there is no reliable method to specifically manipulate them. Although the field of epigenetics has traditionally focused on DNA methylation and chromatin changes, other cellular mechanisms also play important roles in controlling stable switches between various cell fates. Here I propose an innovative approach to program intrinsic small RNA pathways to experimentally affect epigenetic states. I will study how small RNA pathways can be programmed to modulate gene expression and cause heritable phenotypic changes with the ultimate goal of developing small RNA-based tools and methodologies to direct and maintain cellular fates. I will also investigate the crosstalk between small RNA- mediated processes and chromatin-based pathways with the goal of using small RNAs to induce chromatin changes at a specific locus. Investigation of RNA-based epigenetic mechanisms will further our understanding of how cellular fates are selected and fixed during normal development. The methods developed will allow modulation of cellular states with precision and specificity while preserving the underlying DNA sequence. Achievement of these goals will be of great importance for both general science and medicine, as these results will provide insights into processes of development and lineage commitment and allow major advances to be made in medical applications of stem cell technologies and anti-cancer therapies. Public Health Relevance: I will study how the small RNA pathways can be programmed to modulate gene expression and cause heritable phenotypic changes, with the ultimate goal of developing tools and methodologies to direct and maintain cellular fates. Achievement of these goals will be of great importance for both general science and medicine, as it will provide insights into processes of development and lineage commitment and allow major advances to be made in medical applications, such as stem cell technologies and anti-cancer therapy.